Intracellular pH (pH_i) is critical to cardiac excitation and contraction; uncompensated changes in pH_i impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH_i regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl⁻/HCO₃⁻ exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH_i, but also cardiac excitability.

To test the mechanistic role of Slc26a6 in the heart, we took advantage of Slc26a6 knockout (Slc26a6^−/−) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of Slc26a6 results in action potential shortening. There are reduced Ca²⁺ transient and sarcoplasmic reticulum Ca²⁺ load, together with decreased sarcomere shortening in Slc26a6^−/− cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH_i is elevated in Slc26a6^−/− cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl⁻/HCO₃⁻ exchange activities of Slc26a6. Moreover, Slc26a6^−/− mice show evidence of sinus bradycardia and fragmented QRS complex, supporting the critical role of Slc26a6 in cardiac conduction system.

Our study provides mechanistic insights into Slc26a6, a unique cardiac electrogenic Cl⁻/HCO₃⁻ transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH_i, excitability, and contractility. pH_i is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6^−/− mice.